The present invention relates to a process for producing hydroxylated plasma-polymerized films, and the hydroxylated plasma-polymerized films produced by the process of the invention. In addition, the present invention is directed to the use of the hydroxylated plasma-polymerized films produced by the process of the invention for enhancing the compatibility and/or implantability of blood-contacting biomedical implants and devices.
More particularly, the present invention relates to a process for producing films of plasma-polymerized polymers, such as plasma-polymerizing N-vinyl-2-pyrrolidone (PPNVP), deposited on the surface of various implantable devices, and reducing the carbonyl groups present on the crosslinked plasma-polymerized polymer, i.e. the plasma-polymerized N-vinyl-2-pyrrolidone (a polymer which is rich in carbonyl groups), to hydroxyl groups through the use of an aqueous solution of sodium borohydride. By increasing the hydroxyl content of the plasma-polymerized N-vinyl-2-pyrrolidone polymer, the surface upon which the polymer has been deposited exhibits, either alone or in combination with other surface modification agents, increased blood compatibility (i.e. exhibits a decrease in surface induced thrombosis) thereby producing an effective interface for implanted material.
Along this line, surface activated thrombosis and associated sequelae is a major problem which is common to all blood contacting synthetic implants and biomedical devices. All currently used blood-contacting biomaterials suffer from problems associated with surface induced thrombosis such as thrombotic occlusion of the device, and the generation of thromboemboli. The mechanisms of coagulation and platelet activation are common to all "foreign" surfaces in contact with blood, although the kinetics of the reactions are affected by the site of implantation, and the surface area and properties of the material. Examples include implants such as heart valves, ventricular assist devices, vascular grafts; extracorporeal systems such as cardiopulmonary bypass, and hemodialysis; and invasive treatment and diagnostic systems which involve the use of various catheter systems. Other vascular implants such as small diameter vascular grafts are currently impracticable, because of thrombosis problems. Currently, recipients of vascular implants and devices usually undergo aggressive collateral treatment with anticoagulant, antiplatelet and/or fibrinolytic agents to minimize thrombosis. These therapies are not completely effective and the patient may also suffer from significant adverse side effects, which include bleeding and thrombocytopenia.
The lack of a suitable non-thrombogenic biomaterial (biologic or synthetic) has been responsible for limiting progress and success of existing devices and the development of new devices for long-term cardiovascular applications. In this regard, the surface of a biomaterial is the most important factor that affects blood compatibility behavior. This may be the surface of an implanted artificial device such as a heart valve or vascular graft, a blood monitoring device such as a biosensor, or an extracorporeal system such as cardiopulmonary bypass. The potential clinical success of these implantable devices would be greatly enhanced by a nonthrombogenic biomaterial.
A review of the prior art directed to the compatibility of the surface structure of the implantable device indicates that the composition and structure of solid polymer surfaces dominate such properties as (i) wetability (Zisman, W. A., In Adhesion Science and Technology, Lee, L. H., Eds., Plenum Press, N.Y., pp. 55, 1975; Anderson, A. W., Physical Chemistry of Surfaces, John Wiley, N.Y., 1982; and, Cherry B. W., Polymer Surfaces, Cambridge University Press, N.Y., 1981), (ii) adhesion (Anderson, A. W., Physical Chemistry of Surfaces, John Wiley, N.Y., 1982; Cherry B. W., Polymer Surfaces, Cambridge University Press, N.Y., 1981; and, Mittal, K. L., In Adhesion Science and Technology, Lee, L. H., Ed., Plenum Press, N.Y., p. 129, 1975), (iii) friction (Anderson, A. W., Physical Chemistry of Surfaces, John Wiley, N.Y., 1982; and Cherry B. W., Polymer Surfaces, Cambridge University Press, N.Y., 1981), (iv) permeability (Stannet, V., Hopfenberg, H. B., Williams, J. L., In Structure and Properties of Polymer Films, Lenz R. W., Stein, R. S., Eds., Plenum Press, N.Y., p. 321, 1973) and biocompatibility (Anderson, J. M., Kottke-Marchant, K., CRC Crit. Rev. Biocompat., 1, 111, 1985; and Salzman, E. W., Interaction of the Blood with Natural and Artificial Surfaces, Dekker, New York, 1981) Consequently, procedures for the surface modification of materials to improve interfacial properties are of considerable technological importance. One approach has been the use of plasma-polymerization (Boenig, H. V., Plasma Science and Technology, Cornell University Press, Ithaca, 1982) also referred to as glow discharge polymerization.
Plasma-polymerized films can be prepared with a wide range of compositions (Yasuda, H., Plasma Polymerization, Academic Press, New York, 1985) and surface energies (Yasuda, H., Plasma Polymerization, Academic Press, New York, 1985; and Haque, Y., Ratner, B. D., J. Appl. Polym. Sci., 32, 4369, 1986) through the choice of the monomer and the discharge reaction conditions. The deposition is largely independent of the substrate materials and is surface specific, so that a polymer (or other material) can be modified with little effect to its bulk properties.
However, while plasma-polymerization does have several attractive advantages over other methods of surface modification, there is a significant lack of chemical control over the polymer product. Reactions in the low-temperature plasmas are dominated by electron impact events such as ionization and dissociation, with active species reacting and recombining in the plasma and at the substrate surface. Because of the high energies involved in the process, this technique does not provide films with well-defined structures and specific functional groups (Soluble polymers often with high molecular weights can be prepared using the related technique of plasma-initiated polymerization. For a recent detailed report on this technique, see: Paul, C. W., Bell, A. T., Soong, D. S., Macromolecules, 20, 782, 1987). In addition, plasma-polymerized films prepared from monomers with oxygen or nitrogen functional groups invariably are poly-functional, cross-linked, heterogeneous polymers.
Nevertheless, the objective of the studies of the present inventors was to prepare plasma-polymerized films with a well-defined functional group that could serve as a reactive site for further modification. The common approaches for introducing specific functional groups into plasma polymers have been to vary the monomer and discharge conditions or to use or include a gas such as CO.sub.2 (Inagaki, N., Matsunaga, M., Polym. Bull., 13, 349, 1985) or NH.sub.3 (Nakayama, Y., Takahagi, T., Soeda, F., Hatada, K., Nagaoka, S., Suzuki, J., Ishitani, A., J. Polym. Sci., Polym. Chem., 26, 559, 1988), which tend to increase carboxyl and amine groups, respectively. However, these reactions do not normally proceed to high yield with respect to a specific functional group. (Nakayama, Y., Takahagi, T., Soeda, F., Hatada, K., Nagaoka, S., Suzuki, J., Ishitani, A., J. Polym. Sci., Polym. Chem., 26, 559, 1988) have reported that primary amine in NH.sub.3 plasma treated polystyrene was 15%-20% of total nitrogen content. Plasma treatment, as opposed to plasma-polymerization, refers to the use of a non-polymerizing gas plasma to oxidize or otherwise directly treat a polymer surface. No polymer is formed by this process, but the surface composition becomes significantly different from the bulk polymer.
A novel alternative approach to functionalize a plasma-polymerized material is to take advantage of the functional group that is easily generated in the process: carbonyl groups. Plasma polymers derived from oxygen-containing monomers are invariably rich in carbonyl, regardless of the initial monomer structure. Thus, if a polymer or nonorganic was surface modified by plasma-polymerization, carbonyl groups in the modified layer could then be derivatized to introduce a desired functional group.
The major difficulty of this approach is associated with the very poor solubility of cross-linked plasma polymers in organic solvents. Derivatization has to be accomplished across an ill-defined interface between a constrained solid polymer and the liquid reaction medium. However, Whitesides et al. (Rasmussen, J. R., Stedronsky, E. R., Whitesides, G. M., J. Am. Chem. Soc., 99, 4736, 1977; Rasmussen, J. R., Bergbreiter, D. E., Whitesides, G. M., J. Am. Chem. Soc., 99, 4746, 1977), carried out several derivatization procedures on chromic acid oxidized polyethylene. These included the surface reduction of carboxyl to hydroxyl by using diborane in THF and by using an etheral solution of lithium aluminum hydride (Rasmussen, J. R., Stedronsky, E. R., Whitesides, G. M., J. Am. Chem. Soc., 99, 4736, 1977). More recently, Dias and McCarthy (Dias, A. J., McCarthy, T. J., Macromolecules, 17, 2529, 1984) reported a series of surface-specific (i.e., 300-.ANG. depth) derivatization reactions performed on fluorocarbon and fluorochlorocarbon polymers. In each of these previous studies the objective was to introduce specific functional groups into the surface of relatively unreactive solid polymers. Their results hint that derivatization of a plasma-polymerized polymer may possibly be feasible, depending on the effect of the additional geometric constraint imposed by the cross-links in a plasma polymer.
In the present invention, the applicants have focused on the formation of hydroxyl groups by the reduction of the carbonyl groups in plasma-polymerized polymers such as N-vinyl-2-pyrrolidone (PPNVP), a polymer which is rich in carbonyl groups. To applicants' knowledge, the bulk reduction or chemical modification of a cross-linked plasma-polymerized polymer has not been previously reported and/or utilized, particularly for enhancing the surface compatibility of biomedical implants. While the invention shall be described in connection with plasma-polymerized N-vinyl-2-pyrrolidone, it is well understood by those skilled in the art that the process and techniques disclosed herein are not limited to N-vinyl-2-pyrrolidone and may also be applicable to other oxygen-containing monomers such as ethanol and acetone.